Atypical Hemolytic Uremic Syndrome-Associated FHR1 Isoform FHR1*B Enhances Complement Activation and Inflammation.
Atypical Hemolytic Uremic Syndrome-Associated FHR1 Isoform FHR1*B Enhances Complement Activation and Inflammation.
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DOI：
10.3389/fimmu.2022.755694
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发表时间：
2022
影响因子：
7.3
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Xu B;Kang Y;Du Y;Guo W;Zhu L;Zhang H
非典型溶血性尿毒综合征（阿胡斯）是一种罕见但严重的血栓性微血管病，由补体旁路途径的异常激活引发。已有研究报道CFHR 1的三个完全连锁的编码变体形成两种单倍型，即CFHR 1 *A（c.469C，c.475C，c.523G）和CFHR 1 *B（c.469T，c.475G，c.523C）。CFHR 1 *B与阿胡斯易感性相关。为了探索CFHR 1亚型导致阿胡斯的遗传机制，我们通过同源建模比较了FHR 1 *A和FHR 1 *B的结构，发现SCR 3和SCR 4-SCR 5之间的角度存在差异，因为FHR 1 *B的角度大于FHR 1 *A。然后，我们表达了FHR 1 *A和FHR 1 *B重组蛋白，并比较了它们在补体系统调节和炎症中的功能。我们发现FHR 1 *B比FHR 1 *A具有更高的结合C3 B和坏死细胞的能力。在辅因子测定中，FHR-1*B对FH介导的辅因子功能的影响比FHR-1*A更强，导致更少的C3 B裂解产物。在C3转化酶测定中，FHR 1 *B与FHR 1 *A相比显示出更强的抑制C3 bB B组装的去调节FH功能的作用。此外，我们还发现FHR 1 *B比FHR 1 *A更能触发单核细胞分泌IL-1β和IL-6。在本研究中，我们发现CFHR 1的变体可能会不同地影响补体激活和无菌性炎症。我们的研究结果提供了一个可能的机制，潜在的易感性，以阿胡斯引起的CFHR 1亚型CFHR 1 *B。
Atypical hemolytic uremic syndrome (aHUS) is a rare but severe type of thrombotic microangiopathy that is triggered by the abnormal activation of the alternative complement pathway. Previous studies have reported that three completely linked coding variants of CFHR1 form two haplotypes, namely, CFHR1*A (c.469C, c.475C, c.523G) and CFHR1*B (c.469T, c.475G, c.523C). CFHR1*B is associated with susceptibility to aHUS. To explore the genetic mechanism by which CFHR1 isoforms contribute to aHUS, we compared the structures of FHR1*A and FHR1*B by homology modeling and found differences in the angles between SCR3 and SCR4-SCR5, as FHR1*B had a larger angle than FHR1*A. Then, we expressed FHR1*A and FHR1*B recombinant proteins and compared their functions in complement system regulation and inflammation. We found that FHR1*B presented a significantly higher capacity for binding C3b and necrotic cells than FHR1*A. In a cofactor assay, the FHR-1*B showed stronger influence on FH mediated cofactor function than the FHR-1*A, resulted in fewer C3b cleavage products. In the C3 convertase assays, FHR1*B showed more powerful effect compared with FHR1*A regarding to de-regulate FH function of inhibition the assembling of C3bBb. Additionally, we also found that FHR1*B triggered monocytes to secrete higher levels of IL-1β and IL-6 than FHR1*A. In the present study, we showed that variants of CFHR1 might differently affect complement activation and sterile inflammation. Our findings provide a possible mechanism underlying the predisposition to aHUS caused by CFHR1 isoform CFHR1*B.
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影响因子：
7.3
作者：
Schäfer N;Grosche A;Reinders J;Hauck SM;Pouw RB;Kuijpers TW;Wouters D;Ehrenstein B;Enzmann V;Zipfel PF;Skerka C;Pauly D
通讯作者：
Pauly D
影响因子：
14.9
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Pieper U;Webb BM;Dong GQ;Schneidman-Duhovny D;Fan H;Kim SJ;Khuri N;Spill YG;Weinkam P;Hammel M;Tainer JA;Nilges M;Sali A
通讯作者：
Sali A
影响因子：
4.4
作者：
Ferreira, Viviana P.;Herbert, Andrew P.;Pangburn, Michael K.
通讯作者：
Pangburn, Michael K.
影响因子：
20.3
作者：
Heinen, Stefan;Hartmann, Andrea;Skerka, Christine
通讯作者：
Skerka, Christine
影响因子：
3.6
作者：
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通讯作者：
Cortés C